As both men and mice age, their immune systems lose the ability to function normally. This project explores the relationship between decline with age in immune responses and natural resistance, and the stem cells whose descendents produce these responses. Whether a significant part of the decline with age is intrinsic in the stem cells is an important and controversial issue. We have developed methods to test maximal levels of specific stem cell functions over a large portion of the lifespan. These tests will be used to determine whether stem cells are affected by aging, and the degree to which their regulation alters with age. We will maintain and improve our well-defined aging mouse colony, distinguishing between primary effects of aging and the changes with age that result from the increasing vulnerability of old individuals to stress and disease. We will continue developing and defining the competitive repopulation assay; currently we can analyze the long-term functional ability of stem cells from many difference donors by competition with a standard dose of distinguishable stem cells in repopulating specific recipient cell compartments. Using this and other assays, we will determine how proliferation, irradiation, and transplantation cause deleterious effects on stem cell lines. We will test whether they have the same mechanism, for example accelerating the aging process by exhausting stem cell proliferative abilities. Stem cells will be studied in vitro as well as in vivo, and long-term functional capacities of stem cells produced in vitro and in vivo will be compared. We will analyze effects of age in both short-term splenic and long-term systemic natural resistance by comparing it with other treatments that reduce natural resistance. These effects will be related to changes with age in NK activity, killing of tumor cells in vivo and to changes in regulatory functions of the hemopoietic system. Finally, we will determine the degree to which changes with age result from alterations in regulatory cell populations and in stromal microenvironments. Our long term objectives are: to determine whether stem cells are capable of continued normal function for indefinite periods of time, to analyze mechanisms causing declines with age in immunohemopoietic functions, and to find and evaluate procedures that retard or reverse these declines.